CN113329746A

CN113329746A - Compounds for the treatment or prevention of pain, inflammation and/or autoimmunity

Info

Publication number: CN113329746A
Application number: CN202080010393.8A
Authority: CN
Inventors: E·卡普兰; R·赫特
Original assignee: Novaremed Ltd
Current assignee: Novaremed Ltd
Priority date: 2019-01-23
Filing date: 2020-01-22
Publication date: 2021-08-31
Also published as: EP3860582B1; IL282718A; PL3860582T3; WO2020152226A1; PT3860582T; BR112021019476A2; SG11202111773QA; CA3118996A1; RS63270B1; AU2020210831A1; ZA202107346B; EP3860582A1; JP2022518288A; DK3860582T3; KR20210119403A; ES2913977T3; US11891350B2; US20220002228A1; IL282718B1

Abstract

The present invention relates to polymorphs of (S, S) -2-N (3-O- (propan-2-ol) -1-propyl-4-hydroxyphenyl) -3-phenylpropylamide, or synonymously designated N- [2- (4-hydroxy-phenyl) - - (2-hydroxy-propoxymethyl) -ethyl ] -3-phenyl-propionamide, and to the treatment or prevention of pain, inflammation and/or autoimmunity, and provides a method for the treatment or prevention of pain, inflammation and/or autoimmunity in human and/or non-human animals, and use of said polymorphs in the preparation of a medicament for the treatment or prevention of pain (preferably nociceptive or neuropathic pain) in human and/or non-human animals, Use in medicine for inflammation and/or autoimmunity.

Description

Compounds for the treatment or prevention of pain, inflammation and/or autoimmunity

The present invention relates to polymorphs of (S, S) -2-N (3-O- (propan-2-ol) -1-propyl-4-hydroxyphenyl) -3-phenylpropylamide, or synonymously designated N- [2- (4-hydroxy-phenyl) -1- (2-hydroxy-propoxymethyl) -ethyl ] -3-phenyl-propylamide, and to the treatment or prevention of pain, inflammation and/or autoimmunity, and provides a method of treatment or prevention of pain, inflammation and/or autoimmunity in human and/or non-human animals, and use of the polymorphs in the preparation of a medicament for the treatment or prevention of pain (preferably nociceptive or neuropathic pain) and/or pain in human and/or non-human animals, Use in medicine for inflammation and/or autoimmunity.

Background

The compound 2-N (3-O- (propan-2-ol) -1-propyl-4-hydroxyphenyl) -3-phenylpropylamide has been disclosed in US 7,754,771 and its use in the treatment or prevention of pain and inflammation has been described in WO 2009/1099850, WO 2011/030105, US 2011/0086910 and WO 2013/084238. The previous disclosure of this compound has been directed to racemates containing all four enantiomers and diastereomers (i.e., (S, S), (S, R), (R, R), and (R, S)). WO 2013/084238 mentions that racemates containing the S enantiomer at chiral positions adjacent to the amide exhibit particularly advantageous properties.

Pain is a multifaceted or multidimensional empirical response to a variety of stimulus conditions. Pain is defined by the International Association for the Study of Pain (IASP) as "unpleasant sensory and emotional experience associated with or described in relation to actual or potential tissue damage".

Pain in animals is often the result of nociception, i.e., the activation of the nervous system by stimulation of nociceptors. Neuropathic pain differs from nociceptive pain in that it involves damage to the nerve that results in a sensation of pain. In central pain, pain is produced in the brain by some form of injury. Occasional pain may be psychogenic, i.e. caused by a psychiatric disorder.

Pain may be acute or chronic. Acute pain is often caused by, inter alia, soft tissue injury, infection, and/or inflammation. Acute pain is used to warn after physical injury or physical failure. Chronic pain may have no apparent cause, or may be caused by a developing disease or imbalance. Chronic pain is defined as a disease of pain; the origin, duration, intensity and specific symptoms may vary.

The physiological pain experience can be grouped according to source and associated nociceptors. Skin pain is caused by injury to the skin or superficial tissues. Skin nociceptors terminate just below the skin and, due to the high concentration of nerve endings, produce well-defined local pain of short duration. Examples of injuries that cause skin pain include: paper cuts, minor (first-degree) burns and tears. Somatic pain originates from ligaments, tendons, bones, blood vessels and nerves. It is detected by the nociceptors of the body. The lack of pain receptors in these areas produces dull pain, undesirable localized pain, which lasts longer than skin pain; examples include sprains and fractures. Myofascial pain is usually caused by trigger points in muscles, tendons and fascia, and may be localized or referred pain. Visceral pain originates in the internal organs or organs of the body. Visceral nociceptors are located in human organs and cavities. The greater absence of nociceptors in these areas produces pain that is generally more painful and longer lasting than somatic pain. Visceral pain is particularly difficult to localize and several injuries to visceral tissues exhibit "traction" pain, in which sensation is localized in an area completely unrelated to the site of injury. Phantom limb pain, a type of referred pain, refers to the sensation of pain from a limb that has been lost or a limb where a person no longer receives a physical signal. Neuropathic pain may be caused by injury or disease to the nerve tissue itself. This can destroy the ability of the sensory nerves to transmit the correct information to the thalamus, so even if pain has no obvious psychological cause, the brain can interpret the stimulus as pain.

Acute pain is generally treated with both a drug or appropriate technique to eliminate the cause of the disease and a drug or appropriate technique to control the sensation of pain (usually an analgesic).

Analgesics are divided into three categories: opioid (narcotic) analgesics, non-opioid analgesics, and adjunctive analgesics. Opioid analgesics are potent analgesics chemically related to morphine. However, opioids have a number of side effects, which are more likely to occur in patients with certain disorders: renal failure, liver disease, Chronic Obstructive Pulmonary Disease (COPD), dementia or other brain disorders. After the initial opioid use, lethargy, constipation, nausea, vomiting and itching are common. In addition to morphine, opioid analgesics known at the time of this writing include: codeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, oxycodone, oxymorphone, pentazocine, and propoxyphene.

Various non-opioid analgesics may also be used at the time of writing. They are generally effective in mild to moderate pain. Most non-opioid analgesics are classified as non-steroidal anti-inflammatory drugs (NSAIDs). An example of an analgesic that is not an NSAID is acetaminophen, commonly known as acetaminophen. Acetaminophen has essentially no anti-inflammatory properties.

NSAIDs are used to treat mild to moderate pain, and may be used in combination with opioids to treat moderate to severe pain. NSAIDs not only relieve pain, but also reduce inflammation that is often associated with and aggravates pain. Although widely used, NSAIDs also have side effects, sometimes even severe side effects, including digestive tract problems, bleeding problems, problems associated with water logging and increased risk of heart disease and vascular disease. Current NSAIDs include: aspirin, ibuprofen, ketoprofen, naproxen, cyclooxygenase-2 (cox-2) inhibitors, such as celecoxib, choline magnesium trisalicylate, diflunisal, salsalate, diclofenac, etodolac, fenoprofen, flurbiprofen, indomethacin, ketorolac, meclofenamate, mefenamic acid, meloxicam, nabumetone, oxaprozin, piroxicam, sulindac, and tolmetin.

The auxiliary analgesic comprises: antidepressants, such as imipramine, amitriptyline, bupropion, desipramine, fluoxetine, and venlafaxine; anticonvulsants (such as carbamazepine, gabapentin, and pregabalin) and oral and topical local anesthetics.

In the treatment of chronic pain, the world health organization developed "three-step analgesia" is often used. For mild pain, acetaminophen, aspirin or other NSAIDs may be used. For mild to moderate pain, weak opioids (such as codeine and dihydrocodeine) may be used in combination with acetaminophen, aspirin or other NSAIDs. In the case of moderate to severe pain, strong opioids (such as morphine, diacetylmorphine or fentanyl, hydromorphone, methadone, oxycodone or benzazole) may be administered in combination with acetaminophen, aspirin or other NSAIDs.

For neuropathic pain, currently available therapies have only low to moderate efficacy, and many patients do not have significant pain relief. The lack of adequate pain relief for millions of people with neuropathic pain and other types of pain represents a tremendous unmet medical need that is addressed by the present invention.

Disclosure of Invention

The present invention relates to polymorphs of (S, S) -2-N (3-O- (propan-2-ol) -1-propyl-4-hydroxyphenyl) -3-phenylpropylamide, and to the treatment or prevention of pain, inflammation and/or autoimmunity, and provides a method for the treatment or prevention of pain, inflammation and/or autoimmunity in human and/or non-human animals, and the use of the polymorphs in the manufacture of a medicament for the treatment or prevention of pain (preferably nociceptive or neuropathic pain), inflammation and/or autoimmunity in human and/or non-human animals. More specifically, the compounds used in the present invention are compounds having the following chemical formula:

it is the (S, S) isomer of 2-N (3-O- (propan-2-ol) -1-propyl-4-hydroxyphenyl) -3-phenylpropylamide.

The present invention relates to polymorphs of this compound. Polymorphs of this compound are useful in the present invention. This polymorph, hereinafter also referred to as polymorph 2, can be characterized by methods such as X-ray, DSC and/or raman spectroscopy.

As discussed later, it was surprisingly found that polymorph 2 is less hygroscopic, more stable and more readily bioavailable than other crystalline forms such as polymorph 1.

Drawings

FIG. 1: an X-ray powder diffraction pattern of polymorph 2;

FIG. 2: SEM photograph of polymorph 2;

FIG. 3: raman spectra of polymorph 2 measured on Bruker RFS 100/S at 1064 nm;

FIG. 4: TGA/DTA data for polymorph 2;

FIG. 5: table of analytical data for polymorph 1;

FIG. 6: table of analytical data for polymorph 2;

FIG. 7: pre-dose body weights, and calculated doses of form 1(141232) and form 2(COEN4-091-M) of nrd135s.e1 after oral administration of form 1(141232) and form 2(COEN4-091-M) of nrd135s.e1 to male beagle dogs at a target dose level of 60 mg/kg;

FIG. 8: actual blood sampling time after oral administration of form 1(141232) and form 2 of nrd135s.e1 (COEN4-091-M) at a target dose level of 60mg/kg at week 2;

FIG. 9: mean and individual plasma concentrations of nrd135s.e1 after oral administration of form 1(141232) and form 2 of nrd135s.e1 (COEN4-091-M) at a target dose level of 60 mg/kg;

FIG. 10: mean and individual pharmacokinetic parameters of form 1(141232) and form 2 of nrd135s.e1 (COEN4-091-M) in male beagle plasma after oral administration at a nominal dose of 60mg/kg at week 1;

FIG. 11: mean and individual pharmacokinetic parameters of form 1(141232) and form 2 of nrd135s.e1 (COEN4-091-M) in male beagle plasma after oral administration at a nominal dose of 60mg/kg at week 2;

FIG. 12: mean plasma concentrations of form 1(141232) and form 2 of nrd135s.e1 (COEN4-091-M) in male beagle dogs after oral administration at a nominal dose of 60 mg/kg;

FIG. 13: individual plasma concentrations of form 1(141232) of nrd135s.e1 in male beagle dogs after oral administration at a nominal dose of 60mg/kg (order 1-1 old);

FIG. 14: individual plasma concentrations of form 2 of nrd135s.e1 (COEN4-091-M) in male beagle dogs after oral administration at a nominal dose of 60mg/kg (sequence 2-1 new);

FIG. 15: individual plasma concentrations of form 2 of nrd135s.e1 (COEN4-091-M) in male beagle dogs after oral administration at a nominal dose of 60mg/kg (sequence 1-2 new);

FIG. 16: individual plasma concentrations of form 1(141232) of nrd135s.e1 in male beagle dogs after oral administration at a nominal dose of 60mg/kg (sequence 2-2 old);

FIG. 17: process for preparation of (S, S) -2-N (3-O- (propan-2-ol) -1-propyl-4-hydroxyphenyl) -3-phenylpropylamide¹H-NMR spectrum.

Detailed Description

The present invention relates to a polymorph of a specific compound and to the treatment or prevention of pain, inflammation and/or autoimmunity and provides a method for the treatment or prevention of pain, inflammation and/or autoimmunity in a human and/or non-human animal and the use of the polymorph for the manufacture of a medicament for the treatment or prevention of pain (preferably nociceptive or neuropathic pain), inflammation and/or autoimmunity in a human and/or non-human animal. More specifically, the compounds used in the present invention are compounds having the following chemical formula:

this compound ((S, S) -2-N (3-O- (propan-2-ol) -1-propyl-4-hydroxyphenyl) -3-phenylpropylamide), including enantiomers and diastereomers thereof, can be prepared as described in WO 2013/084238 (which is incorporated herein by reference, particularly examples 1 and 2 thereof).

The (S, S) -2-N (3-O- (propan-2-ol) -1-propyl-4-hydroxyphenyl) -3-phenylpropylamide used in the present invention is an enantiomer, which is preferably substantially free of other stereoisomeric forms of the compound. Representative substantially pure enantiomers contain greater than 90 weight percent of one enantiomer of the compound and less than 10 weight percent of another stereoisomeric form of the compound; preferably more than 95% by weight of one enantiomer of the compound and less than 5% by weight of the other stereoisomeric form of the compound; even further preferred is more than 98 wt% of one enantiomeric form of the compound and less than 2 wt% of the other stereoisomeric form of the compound. The term "other stereoisomeric forms" generally refers to the (S, R), (R, S) and (R, R) enantiomeric or diastereomeric forms of the compound 2-N (3-O- (propan-2-ol) -1-propyl-4-hydroxyphenyl) -3-phenylpropylamide. The substantially pure (S, S) -enantiomer is capable of activating BLK and LynA tyrosine kinases with no or substantially no effect on the activity of the LynB tyrosine kinase.

Polymorphs of this compound are useful in the present invention. This polymorph, hereinafter also referred to as polymorph 2, can be characterized by methods such as X-ray, DSC and/or raman spectroscopy.

The inventors have surprisingly found that polymorph 2 is less hygroscopic and more stable than other crystalline forms, such as polymorph 1 discussed later. Furthermore, it was surprisingly found that polymorph 2 has a better bioavailability than polymorph 1. This is particularly surprising in view of its higher stability. Thermal analysis of polymorph 2 showed an initial melting point at 104.5 ℃ and a melting point peak at 107.2 ℃. Melting enthalpy Δ H_MeltingIs about 121J/g.

The thermal analysis used to determine the melting point and enthalpy of fusion of the claimed polymorph can be performed by: using a TGA/DTA analyzer (e.g., Perkin-Elmer STA 600TGA/DTA analyzer)The sample is heated at a temperature of 25 ℃ at a rate of 10 ℃/min, typically from 25 ℃ to 300 ℃, during which time the weight change and Differential Thermal Analysis (DTA) signal is monitored, and the purge gas used is nitrogen at a flow rate of 20cm³/min。

Scanning Electron Microscopy (SEM) showed that polymorph 2 had a regular rectangular block habit with particle sizes of 2-10 μm long and 2-5 μm wide. Particle size is usually expressed as D measured using laser diffraction₅₀Volume median particle diameter.

Gravimetric Vapour Sorption (GVS) showed that polymorph 2 had only a slight hygroscopicity, with a weight gain of 0.6% for 80% RH.

Polymorph 2 of the present invention can be isolated by preparing a slurry in water and crystallizing from a mixture of 50/50 weight ratios of methanol and water. It can also be prepared by rapidly cooling a solution in chloroform and isopropyl acetate.

Polymorph 2 of the present invention typically has an X-ray powder diffraction pattern (cuka) comprising peaks at 19.0 ± 0.2 ° 2 Θ, more preferably at 19.0 ± 0.1 ° 2 Θ, even more preferably at 19.0 ± 0.05 ° 2 Θ. More preferably, the polymorph has an X-ray powder diffraction pattern (CuK α) further comprising one or more peaks selected from the group consisting of peaks at 11.25 ± 0.2 °, 17.38 ± 0.2 °, 17.57 ± 0.2 °, 20.74 ± 0.2 °, 20.91 ± 0.2 °, 22.42 ± 0.2 ° and 23.30 ± 0.2 ° 2 θ. Even more preferably, the other peaks are selected from the group consisting of 11.25 + -0.1 °, 17.38 + -0.1 °, 17.57 + -0.1 °, 20.74 + -0.1 °, 20.91 + -0.1 °, 22.42 + -0.1 ° and 23.30 + -0.1 ° 2 θ. Still more preferably, the peaks are selected from 11.25 ± 0.05 °, 17.38 ± 0.05 °, 17.57 ± 0.05 °, 20.74 ± 0.05 °, 20.91 ± 0.05 °, 22.42 ± 0.05 and 23.30 ± 0.05 ° 2 Θ. Preferably, the peak at 19.0 ± 0.2 ° 2 θ, more preferably at 19.0 ± 0.1 ° 2 θ, is the peak having the highest relative intensity (particularly in the range of 5 to 40 ° 2 θ) in the X-ray powder diffraction pattern (CuK α) of polymorph 2.

Polymorph 2 preferably does not contain any peaks in the range of 15 ± 0.3 ° 2 θ and 16.5 ± 0.2 ° 2 θ. More preferably, polymorph 2 does not contain any peaks in the range of 15 ± 0.5 ° 2 θ and 16.5 ± 0.3 ° 2 θ.

Even more preferably, the polymorph 2 of the invention has an X-ray powder diffraction pattern (CuK α) substantially as shown in figure 1.

The melting point of polymorph 2 is typically in the range of about 105 ℃ to about 110 ℃. Further preferably, the melting point is in the range of about 106 ℃ to about 109 ℃, preferably in the range of about 107 ℃ to about 108 ℃.

In addition to the above, it was even more surprising to find in dog bioavailability tests that the bioavailability of polymorph 2 of the present invention was exceptionally high, in particular higher than that of polymorph 1, as described in the experimental data described herein.

In contrast, the characteristics of polymorph 1 show higher hygroscopicity and lower stability than polymorph 2 of the present invention.

That is, thermal analysis of polymorph 1 showed an initial melting point at 119.6 ℃ and a melting point peak at 125.6 ℃. Melting enthalpy Δ H_MeltingIs about 19J/g.

Simultaneous Thermal Analysis (STA) data for polymorph 1 further showed that between 90-115 ℃, weight loss was small, slightly below 1%, and subsequently in a single Thermal event melting started at-119.5 ℃. Thus, polymorph 1 may be a partial hydrate.

Scanning Electron Microscopy (SEM) showed that polymorph 1 had a majority of particles with irregular shapes and widths of less than 10 μm.

Gravimetric Vapor Sorption (GVS) showed that polymorph 1 is hygroscopic, increasing its weight by-1.3% for 70% RH. However, the weight gain after rapid water uptake was 5.6% between 70% RH to 80% RH and there was a lag (gap) between the adsorption and desorption cycles, suggesting that the format changed. This different form appears to be more hygroscopic, with the second adsorption cycle showing a satisfactory limit of weight gain well above 2% at RH only 40%.

Polymorph 1 can be prepared by recrystallization from various solvents (e.g., methanol, ethanol, 2-propanol, acetonitrile, acetone, 1, 4-dioxane, and dimethylformamide).

Medical application

The invention also relates to the use of polymorph 2 as a medicament and to the use of polymorph 2 in the treatment or prevention of a disease selected from pain, inflammation and autoimmunity. The disease is preferably pain.

Furthermore, the present invention comprises a pharmaceutical composition for the treatment or prevention of pain, inflammation and/or autoimmunity, wherein said composition comprises a pharmaceutically effective amount of polymorph 2, and optionally one or more pharmaceutically acceptable excipients. Additionally or alternatively, the pharmaceutical composition of the invention is provided for the treatment or prevention of inflammation.

The pharmaceutical composition is preferably formulated in a unit dosage form. The unit dosage form preferably comprises from 0.1mg to about 500mg of polymorph 2.

The polymorphs of the present invention are useful for the treatment or prevention of acute or chronic pain. For example, the polymorph can be used to treat nociceptive pain, such as skin pain, somatic pain, myofascial pain, visceral pain, phantom limb pain, or neuropathic pain. The polymorphs described herein are also useful in the treatment of headache or migraine. The polymorph can be used alone or in combination with acetaminophen or another NSAID to treat mild chronic pain, or in combination with a weak or strong opioid to treat moderate or severe pain.

The polymorphs of the present invention may also be used to treat or prevent neuropathic pain and may be used in combination with one or more antidepressants or antiepileptics (e.g., gabapentin or pregabalin). Thus, according to a further aspect of the present invention there is provided a method for the treatment or prevention of pain, inflammation and/or autoimmunity in a human or non-human animal patient, which comprises administering to said patient in need thereof a therapeutically effective amount of a polymorph according to the present invention. For human patients, the polymorph in pure, substantially pure or partially pure form as described in more detail below may suitably be administered in a daily dose of 1.0mg to 15 g. The polymorph can be administered under the supervision of a medical practitioner in an amount sufficient to achieve effective pain management. In some embodiments, the daily dose of the polymorph can be titrated to determine such an effective amount. The daily dose may comprise from about 5.0mg to 1g, typically from about 5mg to 500 mg. In some embodiments, the dose may comprise from 10mg to 100mg of the polymorph per day. The polymorph can be administered on a regimen of 1-4 times per day. The polymorph can be administered parenterally, transdermally, intramuscularly, intravenously, intradermally, intranasally, subcutaneously, intraperitoneally, intraventricularly, intrathecally, or rectally. Preferably, the polymorph is administered orally. Optionally, the polymorph of the invention may be administered simultaneously, sequentially or separately with at least one opioid analgesic, antidepressant or antiepileptic drug. Alternatively, the polymorph of the invention may be administered simultaneously, sequentially or separately with one or more other NSAIDs or acetaminophen.

The polymorphs of the present invention are useful in the treatment or prevention of autoimmune, i.e. autoimmune, diseases. In a preferred embodiment of the invention, the autoimmune disease is celiac disease, type I diabetes, sarcoidosis, Systemic Lupus Erythematosus (SLE), sjogren's syndrome ((SLE))

syndrome), eosinophilic granulomatous polyangiitis, Hashimoto's thyroiditis, Graves ' disease, idiopathic thrombocytopenic purpura, Addison's disease, Rheumatoid Arthritis (RA), ankylosing spondylitis, Polymyositis (PM), Dermatomyositis (DM) or Multiple Sclerosis (MS).

The invention also relates to the use of a polymorph according to the invention for the preparation of a medicament for the treatment or prevention of pain, inflammation and/or autoimmunity. The medicament may be manufactured for co-administration with one or more of acetaminophen, another NSAID, an opioid, an antiepileptic or an antidepressant. In another embodiment, the present invention provides the use of a polymorph according to the invention in the manufacture of a medicament for the treatment or inflammation.

Advantageously, the polymorphs of the present invention have been found to be effective in reducing or preventing inflammation. It has also been found that the polymorph according to the invention has no or substantially no (i.e. within acceptable limits) detrimental effect on the central nervous system.

In another aspect of the present invention, there is provided a pharmaceutical composition for the treatment or prevention of pain, inflammation and/or autoimmunity, said composition comprising a pharmaceutically effective amount of the polymorph according to the present invention. The composition may further comprise one or more pharmaceutically acceptable excipients. In some embodiments, the composition may further comprise acetaminophen, one or more other NSAIDs, one or more weak or strong opioids, an antidepressant or an antiepileptic drug.

The pharmaceutical compositions of the invention may comprise the polymorph of the invention in pure, substantially pure or partially pure form. In some embodiments, the substantially pure form may comprise at least 95 wt% of the polymorph, such as 96 wt%, 97 wt%, 98 wt%, or greater than 99 wt% of the polymorph.

The composition may be formulated as a tablet, pill, capsule, powder, granule, sterile parenteral solution or suspension, metered aerosol or liquid spray, drop, ampoule, autoinjector, suppository, cream or gel. The composition may be adapted for oral, enteral, parenteral, intrathecal, intranasal, sublingual, rectal or topical administration, or for administration by inhalation or insufflation. Oral compositions such as tablets, pills, capsules or wafers are particularly preferred.

For the preparation of solid dosage forms such as tablets, the polymorph can be mixed with one or more pharmaceutical excipients, for example, conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, or other pharmaceutical diluents such as water, to form a solid preformulation composition containing a substantially homogeneous mixture of the polymorph(s) so that the polymorph(s) are uniformly dispersed throughout the composition, so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

The solid preformulation compositions are then subdivided into unit dosage forms of the type described above, each containing from 0.1mg to about 500mg of the polymorph of the invention. Advantageous unit dosage forms comprise 1-500mg, e.g. 1, 5, 10, 25, 50, 100, 300 or 500mg of the polymorph according to the invention.

When formulated as tablets or pills, the tablets or pills may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill may include an inner dose and an outer dose component, the latter being present in the form of an envelope relative to the former. The two components may be separated by an enteric layer that acts to resist disintegration in the stomach and allows the inner component to pass intact into the duodenum or to be delayed in release. Various materials are known for use in such enteric layers or coatings, including a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate.

Alternatively, the pharmaceutical compositions of the present invention may be formulated in liquid dosage forms for oral administration or administration by injection; such as aqueous solutions, suitably flavored syrups, aqueous or oil suspensions or flavored emulsions with edible oils (e.g., cottonseed oil, sesame oil, coconut oil or peanut oil), as well as elixirs or similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic or natural gums, for example, tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

Furthermore, the present invention relates to a method for the treatment or prevention of pain, inflammation and/or autoimmunity in a human or non-human animal patient in need thereof, wherein said method comprises administering to said patient a therapeutically effective amount of polymorph 2 or a pharmaceutical composition comprising polymorph 2. In this method, polymorph 2 is administered in a daily dose of 0.1mg to 15 g. Polymorph 2 is preferably administered orally.

The following definitions apply throughout the specification unless otherwise specifically indicated.

For example, "treatment" of a disorder or disease can result in cessation of progression of the disorder or disease (e.g., no worsening of symptoms) or delay in progression of the disorder or disease (where cessation of progression is only temporary). "treatment" of a disorder or disease may also result in a partial response (e.g., symptom improvement) or a complete response (e.g., symptom disappearance) of the subject/patient with the disorder or disease. Thus, "treatment" of a disorder or disease may also refer to an improvement in the disorder or disease, which may, for example, result in the cessation of progression or delay in progression of the disorder or disease. Such partial or complete responses may be followed by relapse. It is to be understood that the subject/patient may experience a broad response to treatment (e.g., an exemplary response as described herein above). Treatment of a condition or disease may include, inter alia, curative treatment (e.g., altering the disease, preferably resulting in a complete response and ultimately a cure of the condition or disease) and palliative treatment (including symptom relief).

The terms "prevent" or "preventing" a condition or disease as used herein are also well known in the art. For example, a patient/subject suspected of being susceptible to a disorder or disease may particularly benefit from prevention of the disorder or disease. The subject/patient may have a predisposition to or predisposition to a disorder or disease, including but not limited to a genetic predisposition. Such predisposition may be determined by standard methods or analysis using, for example, genetic markers or phenotypic indicators. It is to be understood that the condition or disease to be prevented according to the present invention has not been diagnosed or cannot be diagnosed in a patient/subject (e.g., the patient/subject does not have any clinical or pathological symptoms). Thus, the terms "prevent" or "prevention" encompass the use of a polymorph according to the invention before any clinical and/or pathological condition is diagnosed or determined or can be diagnosed or determined by an attending physician.

The term "about" preferably means ± 10% of the indicated value, more preferably ± 5% of the indicated value, especially the exact value indicated. For example, the expression "about 100" preferably means a specific value of 100 ± 10% (i.e. 90 to 110), more preferably 100 ± 5% (i.e. 95 to 105), even more preferably 100. If the term "about" is used in conjunction with a range endpoint, it preferably means a range from the lower endpoint, which is 10% lower than the indicated value, to the upper endpoint, which is + 10% higher than the indicated value, more preferably a range from the lower endpoint, which is 5% lower than the indicated value, to the upper endpoint, which is + 5% higher than the indicated value, and even more preferably the precise numerical definitions of the lower endpoint and the upper endpoint. Thus, the expression "from about 10 to about 20" preferably means a range from 9 to 22, more preferably a range from 9.5 to 21, even more preferably a range from 10 to 20. If the term "about" is used in conjunction with the endpoints of open-ended ranges, it preferably refers to the corresponding range beginning with 10% of the lower endpoint or + 10% of the upper endpoint, more preferably the corresponding range beginning with 5% of the lower endpoint or + 5% of the upper endpoint, and even more preferably the open-ended range defined by the precise numerical value of the corresponding endpoint. For example, the expression "at least about 10%" preferably means at least 9%, more preferably at least 9.5%, and even more preferably at least 10%.

The terms "optional," "optional," and "may" mean that the indicated feature may or may not be present. Whenever the terms "optional", "optionally" or "may" are used, the invention specifically relates to both possibilities, i.e. the presence of the respective feature, or alternatively the absence of the respective feature. For example, if one component of the composition is indicated as "optional", the invention specifically relates to both possibilities, i.e. the presence of the corresponding component (comprised in the composition) or the absence of the corresponding component in the composition.

The term "comprising" (or "comprises", "including", "contains", "containing" or "containing") means "including, especially" comprising … … "in addition to other optional elements unless explicitly indicated otherwise or contradicted by context. In addition, the term also includes the narrower meanings of "consisting essentially of … …" and "consisting of … …". For example, the term "a comprises B and C" has the meaning of "a contains, inter alia, B and C", wherein a may also comprise other optional elements (e.g., "a contains B, C and D" would also be encompassed), but the term also includes the meaning of "a consists essentially of B and C" and the meaning of "a consists of B and C" (i.e., no other components than B and C are included in a).

Any parameters referred to herein (e.g., including any amounts/concentrations expressed in "mg/ml" or "% (v/v)", as well as any pH value) should preferably be determined under standard ambient temperature and pressure conditions, in particular at a temperature of 25 ℃ (298.15K) and an absolute pressure of 1atm (101.325 kPa).

It is to be understood that the present invention relates specifically to each and every combination of features and embodiments described herein, including any combination of general and/or preferred features/embodiments.

In this specification, a number of documents including patent applications and scientific literature are cited. The disclosures of these documents, while not considered to be relevant to the patentability of the invention, are incorporated herein by reference in their entirety. More specifically, all cited documents are incorporated by reference to the same extent as follows: as if each individual file were specifically and individually indicated to be incorporated by reference.

Examples

The embodiments of the present invention have been presented for purposes of illustration and not limitation.

Example 1 preparation of- (S, S) -2-N (3-O- (propan-2-ol) -1-propyl-4-hydroxyphenyl) -3-phenylpropylamide Preparation of

(S, S) -2-N (3-O- (propan-2-ol) -1-propyl-4-hydroxyphenyl) -3-phenylpropylamide was prepared as described in WO 2013/084238 and US 2011/0086910.

In the first step, 2g of methyl lactate was reacted with an excess of benzyl bromide to give 880mg of (S) -benzyloxymethyl lactate. The reaction was carried out by slurrying sodium hydride in THF and cooling to about-15 ℃. The reaction mixture was then slowly warmed to room temperature and stirred for about 1-2 hours. The reaction was quenched with saturated ammonium chloride solution and extracted twice with MTBE, then the solvent was removed on a rotary evaporator to give a crude oil. The crude product was purified by column chromatography to give pure (S) -2-benzyloxymethyl lactate. The (R) -2-benzyloxymethyl lactate isomer was present at only 0.93%. By avoiding the presence of moisture in the reaction solution, the yield of this step can be increased.

In the second step, 880mg of (S) -2-benzyloxymethyl lactate obtained in step 1 was reduced using lithium aluminum hydride, to obtain (S) -2-benzyloxypropylene glycol having a purity of 98.7% in a yield of 83.8%. A solution of pure (S) -2-benzyloxymethyl lactate in methylene chloride was stirred, and a lithium aluminum hydride solution was slowly added thereto at about 5 ℃. The reaction was monitored by TLC and quenched very carefully with USP-PW water. No racemization occurred during this step.

Then, in a third step, (S) -2-benzyloxypropylene glycol was reacted with methanesulfonyl chloride in dichloromethane in the presence of triethylamine to give the methanesulfonate ester in 88% yield. The solution from step 2 was stirred in dichloromethane and methanesulfonyl chloride was added dropwise thereto at < 5 ℃. After the addition was complete, the progress of the reaction was monitored by TLC. The reaction was quenched with USP-PW water. After separation of the layers, the aqueous layer was back-extracted with dichloromethane. The dichloromethane layers were then combined and washed 3 times with USP-PW water to remove most of the methanesulfonic acid. No racemization occurred during this step.

In a fourth step, the mesylate (of step 3) was coupled with S-O-benzyl tyrosine alcohol to form the double protected product in 22.7% yield with 97.4% purity. The reaction was carried out using a combination of DMF as solvent and sodium hydride as base at room temperature. After stirring at room temperature for at least 12 hours, the reaction was complete.

In a fifth step, 340mg of the product of step 4 was reduced by hydrogenation in the presence of 10% palladium on carbon catalyst and hydrochloric acid using dichloromethane as solvent at 50 ℃. The reaction was completed in about 4 hours without racemization to give the desired product in 84.3% yield and 98.9% purity. More specifically, the catalyst was removed by filtration, and then the filtrate was concentrated at 33 ℃. The resulting mixture of solid and oil was mixed with ethyl acetate. The resulting slurry was filtered and the solid was washed with ethyl acetate and dried under vacuum at 40-45 ℃ to obtain the desired product.

Example 2 preparation of polymorph 2

(S, S) -2-N (3-O- (propan-2-ol) -1-propyl-4-hydroxyphenyl) -3-phenylpropylamide (500mg) was suspended in water (5mL) and the resulting suspension was shaken and temperature cycled between 40 ℃ and 25 ℃ every 4 hours for 72 hours. The excess water is drained as feasibly as possible using a syringe and needle. Thereafter, the product was dried first by evaporating water at ambient temperature and then dried under vacuum at 50 ℃ until constant weight was reached.

Methods for analyzing polymorphs

X-ray powder diffraction (XRPD)

Approximately 5mg of sample was lightly compressed on an XRPD zero background monoclinic silica sample holder. The samples were then loaded into a philips X-Pert MPD diffractometer and analyzed using the following experimental conditions.

Tube anode: copper (Cu)

Tension of the generator: 40kV

Tube current: 40mA

Wavelength α 1:

wavelength α 2:

starting angle [2 θ ]: 5

End angle [2 θ ]: 50

Continuous scanning

Representative X-ray data is acquired at a slower scan speed in the range of 4-40 ° 2 Θ.

Raman spectroscopy

Raman spectrum

Raman spectra were obtained on a Bruker RFS 100/S using an excitation wavelength of 1064 nm. The sample for analysis is prepared by placing the material in a sample holder and placing it in the spectrometer.

Simultaneous Thermal Analysis (STA)

In this context, Simultaneous Thermal Analysis (STA) refers to the simultaneous application of thermogravimetric analysis (TGA) and Differential Thermal Analysis (DTA) to the same sample in a single instrument.

About 5mg of the sample was accurately weighed into a ceramic crucible and then placed into the chamber of a Perkin-Elmer STA 600TGA/DTA analyzer at ambient temperature (25 ℃). The sample is then heated at a rate of 10 ℃/min, typically from 25 ℃ to 300 ℃, during which time the weight change is monitored as well as the DTA signal. The purge gas used was nitrogen with a flow rate of 20cm³/min

Differential Scanning Calorimetry (DSC)

DSC was studied with Netzsch-DSC 204F1 Phoenix. About 5-6mg of the sample was placed in a DSC pan. The analysis was performed in a sealed aluminum pan with small holes. The sample was heated from 25 ℃ to 125 ℃ at a rate of 10K/min under a nitrogen atmosphere.

Scanning Electron Microscopy (SEM)

Scanning electron microscopy was performed using a Tescan Vega 3 scanning electron microscope operating at 15KV and a slight tilt of 15 °.

Prior to analysis, samples were prepared by adhering them to SEM sample stage (SEM stub) using double-sided carbon impregnated sticky labels supplied by Agar Scientific.

The prepared sample stage was then coated with 15nm gold using a qurum Q150ES sputter coater.

Gravimetric Vapor Sorption (GVS)

Approximately 10mg of the sample was placed in a wire mesh vapor sorption balance and loaded into an "igas corp" vapor sorption balance (Hiden Analytical Instruments). The sample was then dried by maintaining the humidity at 0% until no further weight change was recorded. Subsequently, the sample was subjected to a gradual curve from 0-90% RH in increments of 10% RH, holding the sample at each step until equilibrium was reached (99% step complete). Once equilibrium is reached, the% RH in the device is lifted to the next step and the equilibration process is repeated. After the adsorption cycle was completed, the sample was then dried using the same procedure. The change in weight during the adsorption/desorption cycle is then monitored to determine the hygroscopicity of the sample.

Analysis results of polymorphic forms

The resulting XRPD is shown in FIG. 1. A list of the observed peaks is provided below.

TABLE 1

Measurement of (S, S) -2-N (3-O- (propan-2-ol) -1-propyl-4-hydroxyphenyl) -3-phenylpropylamide before and after crystallization to obtain polymorph 2¹H-NMR spectrum. These hydrogen spectra, if consistent with each other, indicate that no chemical conversion has occurred.

The STA data showed no weight loss, indicating that the sample was not hydrated or solvated. The DTA thermogram (see fig. 4) shows a sharp melting, which starts at about 104.5 ℃.

Scanning Electron Microscopy (SEM) (see FIG. 2) shows that this crystal form has a regular rectangular block habit with particle sizes in the range of 2-10 μm long and 2-5 μm wide.

GVS showed that the sample was only slightly hygroscopic, with a weight gain of 0.6% for 80% RH, indicating that form 2 is less hygroscopic than form 1. There was a dramatic weight loss at 90% RH for both cycles, which may be the result of further crystallization of the amorphous content. At the end of both adsorption/desorption cycles this resulted in an overall weight loss of-1%, but XRPD indicated no change in the polymorph.

Example 3 organisms of polymorphs 1 and 2Utilization degree of

The study was aimed at obtaining plasma samples to compare the bioavailability and pharmacokinetics of the two

different polymorphs

1 and 2 following single oral dosing in 6 dogs. The cross-over design was used for three dogs treated with sequence 1 (polymorph 1 first followed by polymorph 2) and three dogs treated with sequence 2 (polymorph 2 first followed by polymorph 1), with a one week washout period between treatments.

The concentration-time curves after treatment of the two polymorphs are characterized by rapid absorption, with a sharp drop in concentration after peak concentration is reached; the second hump in the curve suggests liver-gut recirculation at 4 hours and later.

The maximum observed concentration (Cmax) and area under the plasma concentration-time curve (AUC) measurements appeared higher for drug exposure after polymorph 2 administration compared to after polymorph 1 administration. The Least Squares (LS) geometric mean estimate of AUC (0- ∞) of polymorph 1 (corrected for 60.0mg dose) was 13170h.ng/mL, and that of polymorph 2 was 20064h.ng/mL (p ═ 0.0016). Corresponding to C_maxThe values (corrected for 60.0mg dose) were 4986ng/mL (polymorph 1) and 11088ng/mL (polymorph 2), respectively (p ═ 0.0009). Thus, the obtained AUC measure had a geometric mean ratio (polymorph 2/polymorph 1) of 1.52 (90% CI: 1.35, 1.71) and the Cmax measure had a geometric mean ratio (polymorph 2/polymorph 1) of 2.22 (90% CI: 1.84; 2.70). If individual parameters are not corrected for dose differences or if unexplained AUC values are analyzed, the results and conclusions from the analysis are indistinguishable. These differences between polymorphs indicate a higher availability of polymorph 2.

Polymorph 1 was supplied by Quay Pharmaceuticals as a white powder and stored in the test equipment at room temperature. A copy of the analytical data sheet for form 1 NRD135s.e1 is shown in figure 5.

Polymorph 2 was prepared as described above. A copy of the analytical data sheet for form 2 NRD135s.e1 is shown in figure 6.

Each polymorph was prepared as a suspension in a carrier of 0.5% w/v HPMC K15M/0.5% w/v Tween 80 in sterile water.

6 male beagle dogs (tattoo nos. 4986, 0964, 3611, 2380, 5002 and 1122, and 001M, 002M, 003M, 004M, 005M and 006M in the study, respectively) weighing 9.5-11.5kg and at the time of administration, and aged 2-7 years, were currently used in this study as part of the animal population (population No. 190431). These dogs were originally obtained from Marshall farm USA (New York, U.S.A.) or Envigo RMS and were bred for scientific procedures. During pre-trials and studies, animals were housed in groups of cages appropriate to the species. The animals were examined veterinarily before being admitted to the study and the results were found to be satisfactory. The holding and study zones have automatic control of photoperiod and temperature. The illumination time is 0700-1900 hours. The temperature and humidity ranges measured during the study were 17.0-21.8 deg.C and 23.4-83.07%, respectively. All animals were weighed and body weights recorded prior to each dose administration. A standard laboratory diet of 200-300g of the known preparation (SDS D3(E) SQC) was allowed to be obtained daily, except for a fasting period from overnight before dosing to 4 hours after dosing. The main pipeline high-quality tap water can be used freely.

The formulation is always prepared on the morning of dosing. Each polymorph was made into a suspension in sterile water for injection at a concentration of 12mg/mL in a carrier of 0.5% w/v HPMC K15M/0.5% w/v Tween 80. The desired volume of carrier is added to a suitable formulation container.

The volume of the required carrier was calculated as follows:

V＝(K×D)×1.25

wherein:

v-final volume

K is the number of kg of dose to be administered

D ═ volume administered (mL/kg)

1.25 ═ preparation excess

The amount required for the test item was accurately weighed. The test items were weighed using the appropriate conversion factor and the following formula:

W＝(C×V×100)/P

wherein:

w is the desired weight (mg)

Target formulation concentration (mg/mL, free base)

V-final volume

Purity of P ═ free base (polymorph 1 ═ 98.1%, polymorph 2 ═ 98.7%)

A small amount of the test item (under magnetic stirring) was then added to the same container as the dose carrier. Next, the formulation was left for 15 minutes under magnetic stirring. The Ultraturrax homogenizer was used at average speed for 15 minutes to obtain a homogeneous suspension. The formulation was then left under magnetic stirring until a homogeneous suspension was obtained. The pH of the formulation was measured and the value recorded. If the pH is below 3, it is adjusted to above level 3 by adding 1M NaOH. After formulation was complete, aliquots of 3X 100. mu.L doses were taken. Dose aliquots and any remaining formulation were stored at-80 ℃ until shipment.

The following table shows a summary of each formulation:

TABLE 2

Each group of 3 male dogs received a single oral polymorph dose administration at a target dose level of 60 mg/kg. After a 1-week washout period, 3 male dogs in each group received another polymorph.

Animals were dosed according to the following table:

TABLE 3

¹Target value

For each group, whole blood samples (approximately 1.0mL) were collected from the jugular vein into NaF/EDTA tubes at the following time points:

before administration; 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 and 25 hours post-dose.

The times given above are target times, respected as much as possible. The actual time of sample collection (and dosing) was recorded (table 2) and used to evaluate pharmacokinetic parameters. Immediately after collection, the blood samples were placed on wet ice. Blood samples were centrifuged as soon as possible (+4 ℃, 1500g, 10 min). The resulting plasma was divided into two aliquots (vial A: 100. mu.L plasma, vial B: residual volume plasma) and stored in appropriately labeled polypropylene tubes in a freezer to maintain a temperature of-80 ℃ until shipment. All plasma samples, remaining dose formulations and dose aliquots were stored in freezer cabinets to maintain a temperature of-80 ℃ until shipment.

Pharmacokinetic (PK) parameters were estimated using a non-compartmental approach consistent with the oral route of administration using Phoenix pharmacokinetic software. All parameters were generated by the individual concentrations of

polymorph

1 and 2 in plasma. The parameters were estimated using the nominal sampling time relative to the start of each dose administration within the allowed deviation (+ -10%). Pre-dose samples below the limit of quantitation (0.5ng/ml) were assumed to be 0 for PK analysis.

The area under the plasma concentration-time curve (AUC) of

polymorphs

1 and 2 was calculated using a linear trapezoidal method with linear interpolation. The terminal elimination phase of each concentration-time curve was determined by visual inspection of the semilog concentration-time plot. Due to irregularities in the curve caused in most cases by enterohepatic recirculation of the drug, only the last two observed concentration values can be used in this calculation. The slope of the terminal elimination phase was determined using log linear regression of the unweighted concentration data. (NR) is not reported as a parameter dependent on the determination of the end elimination phase if the measured coefficient is less than 0.800 and/or extrapolation of AUC to infinity indicates more than 20% of the total area. The parameters described in text table 1 are reported as 3 significant numbers, except for Tmax, which is reported as no more significant than the number needed to account for time. Other parameters are automatically generated by Phoenix, which are not required by the protocol but remain in the original data.

TABLE 4

Statistical analysis was performed on the relative bioavailability of polymorphs. The calculation was carried out according to the FDA guide document (Statistical applications to assessment Bioequivalences) as follows:

after natural log transformation, linear mixed effect model analysis programs were performed on dose differences and unnormalized AUC (0- ∞), AUC (0-t) and Cmax values, including: sequence entries, subjects nested in sequence, cycles and conditions of treatment (polymorphs). In addition, statistical comparisons of terminal elimination constants and their associated half-lives, clearance (CL/F) and volume of distribution (V/F) were made using the same analytical approach. All statistical analyses were used

v 9.4; the SAS code is provided in appendix 3A, while the output of the process is provided in appendix 3B. Using the error variances obtained from the model, the least squares means of the new polymorph and the old polymorph and their 90% CI differences were estimated. Inverse transformations were performed on the point and interval estimates to give an estimate of the ratio of the geometric mean of the new polymorph relative to the old polymorph. For Tmax, the median difference between

polymorph

1 and 2 and its 90% CI were calculated.

All oral administrations of

polymorphs

1 and 2 were carried out without exception. No adverse effects of oral administration were observed in animals dosed at any dose. Details of body weight and dosing are shown in figure 7. All blood samples were collected at or near the target sampling time (+ -6 minutes). The actual blood sampling times are shown in fig. 8. Data generated from plasma samples collected in the testing facility and subsequently shipped to a sponsor's representative for bioanalysis was used to generate pharmacokinetic parameters for

polymorphs

1 and 2. The results of the plasma analysis of the quality control samples provide assurance that the results reported by the sample institute were performed.

The individual plasma concentration results for

forms

1 and 2 are shown in figure 9.

The average and individual pharmacokinetic parameter results for

forms

1 and 2 are shown in fig. 10 and 11. The mean concentration-time curves after oral administration of

forms

1 and 2 are shown in figure 12. Individual concentration-time curves for

forms

1 and 2 are shown in figures 13-16.

After thawing the remaining aliquots from the dosing formulation and each individual final dosing suspension, no homogeneous suspension can be obtained anymore, so that no effective concentration results can be obtained from them.

The overall pattern of concentration time curves between the two polymorphs was similar. Absorption of nrd135s.e1 was rapid following administration of either polymorph. In many cases, the peak plasma concentration has been reached at or before the first sampling time point (0.25 hours), and Tmax will not be longer than 0.5h in any case. Subsequently, the concentration dropped rapidly, reaching a first trough concentration in about 4 hours, which was at most 1/10 of the initially reached concentration. After this time point, consistent with the dog regaining food, the concentration rose again to form a second (low) peak and then fell again. Secondary concentration increases suggest hepatic intestinal recirculation of the drug and have been previously noted in rats (see, e.g., study 12NVMDP1R1), dogs (see study VPT1468) and humans (see study nrd135s. e 1.101). Irregularity of concentration drop prevents accurate estimation of elimination half-life. However, in the same animals, these terminal drops are usually very similar for both polymorphs, providing support for an estimated mean half-life of nrd135s.e1 of about 3-4 hours. Since the extrapolated portion of AUC (0- ∞) is small (no more than 6%), it is still possible to reliably estimate AUC (0- ∞) and thus the treatment parameters CL/F and V/F. The measured amounts of both exposures to drug appeared to be higher after polymorph 2 administration compared to after polymorph 1 administration. For polymorph 1(141232), the Least Squares (LS) geometric mean estimate of AUC (0- ∞) (corrected for 60.0mg dose) was 13170h.ng/mL, and for polymorph 2(COEN4-91-M) this was 20064 h.ng/mL. Corresponding to C_maxThe values (corrected for 60.0mg dose) were 4986ng/mL (polymorph 1) and 11088ng/mL (polymorph 2), respectively. When given polymorph 2, these differences between polymorphs indicate that of nrd135s.e1The usability is higher. Polymorph 2 is thermodynamically more stable than polymorph 1, and such results are unexpected.

The results of the statistical analysis are given in table 6. The new polymorph (polymorph 2) was found to have a higher exposure than the old polymorph (polymorph 1). The AUC least squares geometric mean estimate for the new polymorph was extrapolated to infinity (corrected for dose) < AUCINF _ obs _ D > to 1.52 times that of the old polymorph (90% CI: 1.35, 1.71); this difference was statistically significant (p ═ 0.0016). The difference in maximum concentration was even higher, with a point estimate of 2.22-fold higher Cmax values (corrected for dose differences) for the new polymorph than for the old polymorph (90% CI: 1.84; 2.70). If individual parameters were not corrected for dose differences or if unexplained AUC values were analyzed, the results and conclusions from the analysis are also indistinguishable.

Although the extent of absorption varied significantly, there was no difference in the rate of absorption between the two polymorphs as judged by the time required to reach maximum concentration (Tmax). There was no difference in the rate constant of elimination or half-life observed following administration of the two polymorphs.

The concentration-time curve of nrd135s.e1 after administration of the two polymorphs is characterized by rapid absorption with a sharp drop in concentration after reaching peak concentration; at 4 hours and later, the second hump in the curve suggests hepatic intestinal recirculation.

The maximum observed concentration (Cmax) and area under the plasma concentration-time curve (AUC) appeared higher for the drug exposure measurements after polymorph 2 administration compared to after polymorph 1 administration. The obtained AUC measurements gave a geometric mean ratio (polymorph 2/polymorph 1) of 1.52 (90% CI: 1.35, 1.71) and the obtained Cmax measurements gave a geometric mean ratio (polymorph 2/polymorph 1) of 2.22 (90% CI: 1.84; 2.70). If individual parameters were not corrected for dose differences or if unexplained AUC values were analyzed, the results and conclusions from the analysis did not differ. These differences between polymorphs indicate that the availability of nrd135s.e1 is higher when given as polymorph 2.

Although the extent of absorption varied significantly, there was no difference in the rate of absorption between the two polymorphs, as judged by the time required to reach maximum concentration (Tmax), and no difference in the rate of elimination constant or half-life observed following administration of the two polymorphs.

For a ratio of order 1 to order 2 estimated to be 1.38 (90% CI: 1.06; 1.79), an order was observed to have a correlated but statistically insignificant effect on Cmax. This sequential effect reduces the accuracy with which differences in exposure between the two polymorphs can be estimated.

Claims

1. A polymorph of a compound having the formula:

wherein the polymorph has an X-ray powder diffraction pattern (CuK α) comprising a peak at 19.0 ± 0.2 ° 2 θ.

2. The polymorph of claim 1, wherein the polymorph has a melting point in the range of about 105 ℃ to about 110 ℃.

3. A polymorph of a compound having the formula:

wherein the polymorph has a melting point in the range of about 105 ℃ to about 110 ℃.

4. The polymorph of claim 3, wherein the polymorph has an X-ray powder diffraction pattern (CuK α) comprising peaks, in terms of 2 θ, at about 19.0 ± 0.2 °.

5. The polymorph of any one of claims 1 to 4, wherein the X-ray powder diffraction pattern (CuK α) further comprises one or more peaks selected from 11.25 ± 0.2, 17.38 ± 0.2, 17.57 ± 0.2, 20.74 ± 0.2, 20.91 ± 0.2, 22.42 ± 0.2, and 23.30 ± 0.2 ° 2 θ.

6. The polymorph of any one of claims 1 to 5, wherein a powder X-ray diffraction pattern (CuK α) is substantially as shown in figure 1.

7. The polymorph of any one of claims 1 to 6, wherein the polymorph has a melting point of about 106 ℃ to about 109 ℃, preferably about 107 ℃ to about 108 ℃.

8. The polymorph of any one of claims 1 to 6, wherein the polymorph has an enthalpy of fusion in the range of 100 to 140J/g, preferably 110 to 130J/g, and more preferably 115 to 125J/g.

9. The polymorph of any one of claims 1 to 8 for use as a medicament.

10. Use of a polymorph according to any one of claims 1 to 8 in the treatment or prevention of pain.

11. Use of a polymorph according to any one of claims 1 to 8 in the treatment or prevention of inflammation and/or autoimmunity.

12. A pharmaceutical composition for the treatment or prevention of pain, inflammation and/or autoimmunity, comprising a pharmaceutically effective amount of one or more compounds according to any one of claims 1-8, and optionally one or more pharmaceutically acceptable excipients.

13. The pharmaceutical composition of claim 12, wherein the composition is formulated in a unit dosage form, preferably containing from 0.1mg to about 500mg of the compound or compounds.

14. The pharmaceutical composition according to claim 12 or 13, which is administered orally.

15. A method for the treatment or prevention of pain, inflammation and/or autoimmunity in a human or non-human animal patient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of at least one compound according to any one of claims 1-8 or a pharmaceutical composition according to claim 12 or 13.

16. The method of claim 15, wherein a daily dose of 0.1mg to 15g of the one or more compounds is administered.

17. The method of claim 15 or 16, wherein the one or more compounds are administered orally.